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The role of serotonin in ischemic cellular damage and the infarct size-reducing effect of sarpogrelate, a 5-hydroxytryptamine-2 receptor blocker, in rabbit hearts

Yasuko Shimizu, MD^*, Shinya Minatoguchi, MD^*, Kazuaki Hashimoto, MD^*, Yoshihiro Uno, MD^*, Masazumi Arai, MD^*, Ningyuan Wang, MD^*, Xuehai Chen, MD^*, Chuanjian Lu, MD^*, Genzou Takemura, MD^*, Masaaki Shimomura, MSc, Takako Fujiwara, MD and Hisayoshi Fujiwara, MD^*,*

^* Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan
Kyoto Women’s University, Kyoto, Japan

View larger version (18K): [in a new window]   Figure 1 (A) Myocardial interstitial serotonin levels before, during 30-min ischemia, and during two consecutive 30-min reperfusions in the absence and presence of sarpogrelate in an in vivo model. Myocardial interstitial serotonin levels were significantly increased during ischemia and the first 30-min reperfusion. These increases were inhibited by sarpogrelate. Vertical axis: eluate concentration (ng/ml). *p < 0.05 versus baseline control. (B) Myocardial interstitial serotonin levels before, during 30-min ischemia, and during 30-min reperfusion in an isolated heart model with and without sarpogrelate. Myocardial interstitial serotonin levels were significantly increased during ischemia without sarpogrelate. Sarpogrelate completely abolished the increase in myocardial interstitial serotonin during ischemia. Vertical axis: eluate concentration (ng/ml). *p < 0.05 versus baseline control.

View larger version (14K): [in a new window]   Figure 2 Infarct size as a percentage of the area at risk (AAR). Sarpogrelate (SG) pretreated group: SG was infused at a rate of 5 or 10 mg/kg/h starting 10 min before ischemia until 20 min after reperfusion for 60 min. Sarpogrelate post-treated group: SG was infused at a rate of 10 mg/kg/h starting 10 min before reperfusion until 50 min after reperfusion for 60 min. Sarpogrelate (5 and 10 mg/kg/h) reduced the infarct size, which was blocked by a selective protein kinase C inhibitor, chelerythrine, or a mitochondrial adenosine triphosphate sensitive potassium channel blocker, 5-hydroxydecanoate (5-HD). Chelerythrine or 5-HD alone did not affect the infarct size. *p < 0.05 versus control.

View larger version (35K): [in a new window]   Figure 3 Quantitation of protein kinase C- in the cytosolic and membrane fractions in the control, control + sarpogrelate, ischemia, and sarpogrelate + ischemia groups. *p < 0.05.

View larger version (20K): [in a new window]   Figure 4 Role of serotonin in ischemia and reperfusion and the possible mechanism of the infarct size-reducing effect by sarpogrelate. Serotonin (5-hydroxytryptamine [5-HT]) is released from cardiac tissues within the area at risk, such as platelets in the vascular beds, mast cells, and sympathetic nerve endings, in ischemia and reperfusion. The increase in myocardial interstitial serotonin induces the release of a large amount of serotonin from platelet cytoplasm and platelet aggregation via 5-HT2A receptor on the cell membrane of platelets (#), and the myocardial interstitial serotonin is further increased. Note the presence of a vicious cycle among the released serotonin, 5-HT2A receptors, on the cell membrane of platelets and rich serotonin in platelet cytoplasm. Sarpogrelate, 5-HT2 receptor blocker, inhibits the binding between released serotonin and 5-HT2A receptors on the cell membrane of platelets and blocks the increase in interstitial serotonin by breaking the vicious circle. Translocation of protein kinase C (PKC)- from the cytosolic to the membrane fraction followed by opening of the mitochondrial adenosine triphosphate sensitive potassium channel is an intrinsic protective mechanism of cardiomyocytes against ischemic damage. The released serotonin during ischemia inhibits the translocation of PKC- (*). Sarpogrelate further enhances translocation of PKC- followed by opening of the mitochondrial adenosine triphosphate sensitive potassium channel and reduces infarct size via inhibition of serotonin release.